Timed, pulsatile release systems

ABSTRACT

A unit multiparticulate dosage form for delivering one or more basic, active pharmaceutical ingredients into the body in need of such medications to achieve target PK (pharmacokinetics) profiles is described. The dosage form comprises one or more multicoated drug particles (beads, pellets, mini-/micro-tablets) having a barrier coating and a lag-time coating. Each Timed Pulsatile Release (TPR) bead population exhibits pre-determined lag-time followed by differing release characteristics. The composition and thickness of the barrier coating, composition and thickness of the lag-time coating, ratio of IR beads to one or more TPR bead populations and total dose may be varied depending on the alkalinity, pH-dependent solubility and elimination half-life of the active ingredients to achieve target PK profiles (suitable for a once or twice daily dosing regimen) in patients in need of such medications.

CROSS REFERENCE TO OTHER APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/037,890, filed Jul. 17, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/401,430, filed Jan. 9, 2017 (now U.S. Pat. No.10,045,946, issued Aug. 14, 2018), which is a continuation of U.S.patent application Ser. No. 14/885,647, filed Oct. 16, 2015 (now U.S.Pat. No. 9,579,293, issued Feb. 28, 2017), which is a continuation ofU.S. patent application Ser. No. 11/120,139, filed May 2, 2005, (nowU.S. Pat. No. 9,161,918, issued Oct. 20, 2015), each of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to the development of timed, pulsatilerelease bead populations comprising one or more alkaline pharmaceuticalactives exhibiting release of the drug after a predetermined delay (lagtime) of more than about 5 hours and to the production of oral drugdelivery systems to target PK (pharmacokinetics, i.e., plasmaconcentration-time) profiles suitable for a twice- or once-daily dosingregimen, thereby minimizing potential risks of adverse side effects,enhancing patient compliance and therapeutic efficacy, and reducing costof treatment.

BACKGROUND OF THE INVENTION

Many therapeutic agents are most effective when made available atconstant rates at or near the absorption sites. The absorption oftherapeutic agents thus made available generally results in desiredplasma concentrations leading to maximum efficacy, and minimum toxicside effects. Much effort has been devoted to developing sophisticateddrug delivery systems such as osmotic devices for oral application.However, there are instances where maintaining a constant blood level ofa drug is not desirable. For example, a major objective of chronotherapyfor cardiovascular diseases is to deliver the drug in higherconcentrations during the time of greatest need, e.g., the early morninghours, and in lesser concentrations when the need is less, e.g., duringthe late evening and early sleep hours. In addition to a properlydesigned drug delivery system, the time of administration is equallyimportant. The unique pharmacokinetic profile needed can be calculatedfrom a simulated modeling developed using the pharmacokineticparameters, knowledge of drug solubility, absorption along thegastrointestinal tract and elimination half-life.

A timed, pulsatile delivery system capable of providing one or moreimmediate release pulses at predetermined lag times or at specific sitesresult in better absorption of the active and more effective plasmaprofile. However, there are only a few such orally applicable pulsatilerelease systems due to potential limitations of the dosage form size,and/or polymeric materials and their compositions used for producingdosage forms. Ishino et al. disclose a dry-coated tablet form inChemical Pharm. Bull. Vol. 40 (11), p 3036-3041 (1992). U.S. Pat. No.4,871,549 assigned to Fujisawa Pharmaceutical Company discloses thepreparation of a time-controlled explosion system in which rapid-releasepulses at predetermined time intervals are caused by explosion of themembrane surrounding the drug cores comprising swelling agents such asdisintegrants (e.g., low-substituted hydroxypropylcellulose,crospovidone, crosslinked carboxymethylcellulose, sodium starchglycolate). These systems are rather difficult to manufacture and do notconsistently perform.

U.S. Pat. No. 6,531,152 discloses an explosion-controlled drug deliverysystem comprising a core containing a drug in combination with a corematerial (such as a polysaccharide or a crosslinked protein and adisintegrant that swell on exposure to body fluids or water) having arigid membrane comprising hydrophobic and hydrophilic polymers thatbursts rapidly releasing the active when the core swells. The '152patent discloses specific tablet formulations having lag-times of up toabout 12 hours. U.S. Pat. No. 6,287,599 to Burnside et al. discloses apharmaceutical composition (a tablet formulation) comprising at leastone pharmaceutically active agent that has a pH dependent solubility, atleast one non-pH dependent sustained release agent and at least onepH-dependent agent that increases the dissolution rate of the active ata pH in excess of 5.5. Such a system exhibits approximately pHindependent drug release profile.

However, monolithic drug delivery systems exhibit variablegastrointestinal transit times, and multiparticulate dosage formscontaining coated drug particles (beads, pellets or micro-tablets)exhibiting consistent GI transit times are preferred.

The pulsatile burst release times in the above-described deliverysystems are controlled by choosing appropriate core material, and byvarying the membrane composition and/or thickness. However, it isdifficult to consistently manufacture quality products based on suchdrug delivery systems wherein the drug-release is controlled by aswelling agent, a hydrophobic excipient, an osmotic agent alone ormixtures thereof.

U.S. Pat. No. 6,627,223, assigned to Eurand Pharmaceutical Limited,which is incorporated herein by reference, discloses a pulsatile releasesystem consisting of a combination of one or more bead populations, eachwith a well-defined release profile. A timed, sustained-release profile(i.e., a sustained-release profile over a 12 to 24 hours after alag-time of about 4 hours (i.e., a period of little or no release)following oral administration is disclosed in U.S. Pat. No. 6,500,454,and a biphasic release profile (i.e., an immediate-release pulse and arapid burst after a lag-time of about 3 hours) is disclosed in U.S. Pat.No. 6,663,888. Although, a lag-time of greater than 3 hours could beachieved by applying a membrane comprising a water-insoluble polymersuch as ethylcellulose (Ethocel Standard Premium 10 cps available fromDow Chemical Company) and an enteric polymer such as hydroxypropylmethylcellulose phthalate (HP-55 available from Shin-Etsu ChemicalCorporation, Tokyo, Japan) on drug-layered beads containing propranololhydrochloride (56% drug-load coated on 25-30 mesh sugar spheres) at10-15% weight gain, the same coating composition applied on drug-layeredbeads containing nizatidine (56% drug-load coated on 25-30 mesh sugarspheres) even at 35-39% by weight resulted in a lag-time of less than 3hours. It was considered in the prior art that the solubility oftherapeutic agent in the dissolution medium and/or the molecular weightof the agent determined the drug dissolution within the coated bead andits diffusion out of the membrane. After extensive investigations, itwas surprisingly discovered that apart from pH-dependent solubility ofthe therapeutic agent, its acidity/alkalinity has a significant effecton the lag-time that could be achieved. Additionally, the impact of abarrier coating (i.e., an intermediate coating applied in between theinner protective seal coat and the outer lag time coating, hereafterreferred to as the barrier coat) and/or its composition on lag-time thatcould be achieved can vary depending on the acidity/alkalinity of theactives.

SUMMARY OF THE INVENTION

The present invention provides a pulsatile delivery system suitable fora twice-daily or once-daily dosing regimen by oral administration of aspecific therapeutic agent depending on its acidity/alkalinity,solubility in gastrointestinal fluids, and its elimination half-life.The pulsatile delivery system comprises one or more bead populations,such as immediate release (IR) Beads and timed, pulsatile-release (TPR)bead populations. Each TPR bead population releases the drug as a rapidburst or as a sustained-release profile after a pre-determined lag-time(for example, 10 hours or longer is achievable) upon oraladministration. The IR Beads may be simply drug cores coated with aprotective membrane (for example, a coating with Opadry Clear). These IRBeads with a barrier coating are coated with a functional membrane of amixture of water insoluble and enteric polymers, a plasticized polymericsystem being applied from aqueous or solvent based composition. Thefinished dosage form may be a modified-release (MR) capsule, a standard(conventional) tablet or an orally disintegrating tablet (ODT)comprising a coated spherical bead population containing the activesubstance alone or a combination of two or more coated bead populationsto provide target plasma concentrations suitable for a once ortwice-daily dosing regimen. For example, a once-daily dosage form of anactive with an elimination half-life of about 7 hours may contain amixture of an IR bead population which allows immediate release, asecond, TPR bead population with a shorter lag-time (about 3-4 hours),which allows a delayed “burst” release and a third, TPR bead populationwith a longer lag-time (about 6-9 hours), which allows a delayed,typically sustained-release profile of an active with an eliminationhalf-life of about 7 hours, thus enhancing safety, therapeutic efficacyand patient compliance while reducing cost of treatment. The achievablelag time depends on the composition and thickness of the barriercoating, the composition and thickness of the lag-time coating, as wellas the nature of the therapeutic agent. Specific factors that can affectthe lag-time include, but are not limited to, the therapeutic agent'salkalinity/acidity, solubility, elimination half-life, and dosing(twice-daily or once-daily) regimen.

BRIEF DESCRIPTION OF THE FIGURES

The invention will be described in further detail with reference to theaccompanying Figures wherein:

FIG. 1 shows drug release profiles of nizatidine IR beads (without abarrier coating) coated with EC/HPMCP at 20, 25 and 30% by weight ofExample IC.

FIG. 2 shows drug-release profiles of propranolol hydrochloride IR beads(without a barrier coating) coated with EC/HPMCP at 20, 30 and 40% byweight of Example 2C.

FIG. 3 shows drug release profiles of IR beads (without a barriercoating) coated with EC/HPMCP at 20% by weight (a) propranololhydrochloride and (b) nizatidine and at 30% by weight (c) propranololhydrochloride and (d) nizatidine.

FIG. 4 shows drug release profiles of nizatidine IR beads coated firstwith a barrier coating of HPMCP and then coated with a lag-time coatingat 20, 30 and 40% by weight of Example 1D.

FIG. 5 shows drug release profiles of nizatidine IR beads coated firstwith a barrier coating of EC/HPC and then coated with a lag-time coatingat 20, 30 and 40% by weight of Example 1E

FIG. 6 shows the effect of the barrier coating applied on nizatidine IRbeads on the lag time achieved at a lag-time coating of 30% by weight:(A) None, (B) 10% HPMCP and (C) 5% 70/30 EC/HPC.

DETAILED DESCRIPTION OF THE INVENTION

Active pharmaceutical ingredients (API) typically are either slightlyacidic or basic when suspended in purified water (see Table 1). Theextent of acidity or alkalinity varies significantly. For example, thepH can range from as low as 5.7-6.5 for propranolol hydrochloride to apH of 6.5-8.7 for nizatidine to as high as a pH of 7.9-11.0 foratenolol. An active pharmaceutical ingredient exhibiting a pH of 7.0, orless, when suspended in water at a solid content of 2 mg/mL isdesignated as an acidic drug in this invention disclosure while an APIexhibiting a pH of 7.0, or greater, is designated as an alkaline drug.

TABLE 1 pH of representative drugs suspended in water Acidity/ DrugAlkalinity pH of Solution/Suspension Drug concentration (solid 0.2 mg/mL2.0 mg/mL 20 mg/mL content) Propranolol Acidic pH = 5.7 pH = 6.0 pH =6.5 Hydrochloride Nizatidine Alkaline pH = 6.5 pH = 7.4 pH = 8.7 Drugconcentration (solid 0.1 mg/mL 1.0 mg/mL 10 mg/mL content)Cyclobenzaprine Acidic pH = 6.1 pH = 6.5 pH = 6.7 Hydrochloride AtenololAlkaline pH = 7.9 pH = 10.9 pH = 11.0

Since the polymer blend system typically utilized to delay the onset ofdrug-release by several hours upon oral administration is a mixture ofwater-insoluble and enteric polymers, the extent of delayed onsetdepends on the acidity/alkalinity of the API. The present inventionprovides a method for manufacturing a pharmaceutically elegantmulti-particulate dosage form having timed, pulsatile release profiles,i.e., a well time-controlled single pulse or a series of pulsesoccurring several hours after oral administration. The present inventionalso provides a multicoated, multiparticulate dosage form having anactive core, an intermediate barrier-coating and an outer membrane of amixture of water-insoluble polymer and an enteric polymer. A barriercoating applied on IR beads may comprise an enteric polymer, awater-insoluble polymer or a mixture of water-insoluble andwater-soluble polymers. The polymers used in forming the barrier coatingand the outer membrane may be plasticized.

In accordance with one aspect of the present invention, the active coreof the dosage form may comprise an inert particle, which is coated witha drug-containing film-forming formulation and, in accordance withcertain embodiments, an inert particle is coated with a water-solublefilm forming composition to form a water-soluble/dispersible particle.The amount of drug in the core will depend on the drug and the dose thatis desired. Generally, the core in accordance with this aspect of theinvention will contain about 5 to 60% by weight of the drug based on thetotal weight of the core. Those skilled in the art will be able toselect an appropriate amount of drug for coating or incorporation intothe core to achieve the desired dosage form.

The active core of the dosage form of certain embodiments of the presentinvention may comprise an inert particle such as a sugar sphere with adesired mean particle size. In one embodiment, the inactive core may bea sugar sphere, a cellulose sphere, a spheroidal silicon dioxide bead, abuffer crystal or an encapsulated buffer crystal, such as calciumcarbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. Buffercrystals are useful to alter the microenvironment. Alternatively, inaccordance with other embodiments, drug-containing microgranules orpellets may be prepared by rotogranulation, high-shear granulation andextrusion-spheronization or compression (as mini-/micro-tablets (aboutone/two mm in diameter)) of the drug, a polymeric binder and optionallyfillers/diluents.

Active cores comprising an inert particle coated with a drug-containingfilm forming binder can be prepared in accordance with the followingprocess. An aqueous or a pharmaceutically acceptable solvent medium maybe used for preparing core particles based on coated inert particles.The type of inert binder that is used to bind the water-soluble drug tothe inert particle is not critical but usually water soluble or alcoholsoluble binders, such as polyvinylpyrrolidone (PVP or povidone) orhydroxypropylcellulose may be used. The binder may be used at anyconcentration capable of being applied to the inert particle. Typically,the binder is used at a concentration of about 0.5 to 10% by weight. Thedrug substance may be present in this coating formulation in solutionform or may be suspended. The drug concentration may vary depending onthe application but typically will be used at concentrations from about10 to 30% by weight depending on the viscosity of the coatingformulation.

In accordance with other embodiments, the active core may be prepared byrotogranulation, or by granulation followed by extrusion-spheronizationor tableting into micro-/mini-tablets. The drug substance, a binder, anoptional dissolution rate controlling polymer, and optionally otherpharmaceutically acceptable excipients (e.g., diluents/fillers) may beblended together in a high-shear granulator, such as Fielder granulator,or a fluid bed granulator, such as Glatt GPCG granulator, and granulatedto form agglomerates by adding/spraying a granulating fluid such aswater or alcohol and dried. The wet mass can be extruded and spheronizedto produce spherical particles (pellets) using an extruder/marumerizer.The blend comprising drug particles, a binder and optionally afiller/diluent or drug-containing granules can also be compressed intomini-tablets (about 2 mm in diameter) or micro-tablets (about 1 mm indiameter) to produce IR pellets. In these embodiments, the drug loadcould be as high as 95% by weight based on the total weight of theextruded or granulated core.

Generally, the individual polymeric coatings on the active core willvary from about 1.5 to 60% by weight depending on the nature of theactive, composition of the barrier coat, and required lag-time. In oneembodiment, the core with a high drug-load may be provided with abarrier-coat of a plasticized water-insoluble polymer, such asethylcellulose (EC), at about 1.5-15% by weight to sustain thedrug-release over about 5-20 hours. In certain other embodiments, thecore with a high drug-load may be provided with a barrier-coat of aplasticized enteric polymer, such as hydroxypropyl methylcellulosephthalate (HPMCP), at about 5-20% by weight. In yet another embodimentof the present invention, the active core may be provided with an outerlag-time coating of EC/HPMCP/plasticizer at about 45.5/40/14.5 for aweight gain of about 30-60% by weight to lengthen the lag-time up toabout 10 hours or longer.

Both the barrier and outer (hereafter referred to as lag-time) membranecoatings on water-soluble/dispersible drug containing particles (IRbeads) may comprise a plasticizer. The intermediate or barrier membranemay comprise an enteric polymer such as hydroxypropyl methylcellulosephthalate (HPMCP) or a water-insoluble polymer (e.g., ethylcellulose)alone or in combination with one or more water-soluble/pore-formingpolymer such as HPMC, methyl cellulose, hydroxypropyl cellulose (HPC),polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP). When thebarrier coating comprises a water-insoluble polymer in combination witha water-soluble/pore-forming polymer, the polymers are typically presentat a ratio from about 9:1 to 5:5, water-insoluble polymer towater-soluble polymer. The barrier coating is typically applied for aweight gain of from about 1.5 to 15% by weight.

The outer lag-time membrane may comprise a plasticized mixture of awater-insoluble polymer and an enteric polymer wherein thewater-insoluble polymer and the enteric polymer may be present at aweight ratio of about 10:1 to 1:2 and typically about 3:1 to 1:1. Thetotal weight of the lag coating varies from about 30 to 60% and moreparticularly from about 40 to 55% by weight based on the weight of thecoated bead.

Cores comprising a slightly basic drug, such as nizatidine, may beprovided with only the lag-time coating (no barrier coating) ofEC/HPMCP/plasticizer at about 45.5/40/14.5 for a weight gain of about40% by weight, which may result in a lag-time of about 3 hours or less.In contrast, cores comprising a slightly acidic drug, such aspropranolol hydrochloride, may be provided with only the lag-timecoating of EC/HPMCP/plasticizer at about 45.5/40/14.5 for a weight gainof about 40% by weight, which could result in a lag-time of about 6hours or longer. Those skilled in the art will be able to select anappropriate amount of active for coating onto or incorporating into thecore to achieve the desired dosage.

In accordance with one particular embodiment of the present invention,the water soluble/dispersible drug-containing particle is coated with amixture of a water insoluble polymer and an enteric polymer. The waterinsoluble polymer and enteric polymer may be present at a weight ratioof from about 10:1 to 1:2, more particularly from about 2:1 to 1:1, andthe total weight of the coatings is about 30 to 60% by weight based onthe total weight of the coated beads. The polymeric coatings typicallycontain plasticizers and may be applied from aqueous and/orsolvent-based systems.

The composition of the membrane layer and the individual weights of thepolymers are important factors to be considered for achieving a desiredlag time prior to appreciable drug release. The coated beads mayoptionally have a barrier layer of pharmaceutical glaze (shellac) underthe lag-time coating, which basically dictates the lag time.

The invention also provides a method of making timed, pulsatile releasebeads comprising the steps of:

-   -   1. preparing drug-containing cores by coating inert particles,        such as sugar spheres or cellulose spheres, with one or more        active pharmaceutical ingredients from a polymeric binder        solution/suspension and applying a protective seal-coat to form        immediate release (IR) beads;    -   2. coating the IR beads with a plasticized a) water-insoluble        polymer alone or in combination with a water-soluble polymer        or b) enteric polymer to form barrier-coated beads with a        membrane thickness of from about 1.5% to 20% by weight;    -   3. coating the barrier-coated beads with a plasticized mixture        of a water-insoluble polymer and an enteric polymer with a        membrane thickness of from about 40% to 60% by weight to form        TPR (Timed Pulsatile Release) beads exhibiting a lag-time of up        to about 10 hours or longer; and    -   4. filling two or more bead populations—IR beads and one or more        TPR bead populations, wherein each TPR bead population may        exhibit different lag-times into hard gelatin capsules, or        compressing into conventional tablets or orally disintegrating        tablets, to produce a once-daily or twice-daily capsule        formulation.

The release profiles for IR, barrier-coated and TPR beads may bedetermined according to the following procedure:

Dissolution testing of IR beads and enteric coated beads (for acidresistance testing) is conducted with a USP Apparatus 1 (baskets at 100rpm) or Apparatus 2 (paddles at 50 rpm) in 900 mL of 0.1N HCl at 37° C.while the dissolution testing of TPR beads is conducted in a USPapparatus using a two-stage dissolution medium (first 2 hours in 700 mLof 0.1N HCl at 37° C. followed by dissolution testing at pH=6.8 obtainedby the addition of 200 mL of pH modifier). Drug release with time isdetermined by HPLC on samples pulled at selected intervals.

The TPR Beads prepared in accordance with present invention may bedesigned to provide a target drug-release profile, such as a rapid pulseor a sustained-release profile following a pre-determined lag-time. Evenin the absence of the barrier coating, thicker lag-time coatingstypically provide moderately sustained rather than rapid pulses (seeFIG. 3 for details). The multiparticulate dosage form may be provided asa single TPR bead population alone or a TPR bead population combinedwith an IR bead population and/or one or more additional TPR beadpopulations providing different release profiles. In accordance with oneembodiment, a multiparticulate dosage form is provided with at least anIR bead population, a first TPR population and a second TPR populationwere in the ratio of IR bead to the first and second TPR bead populationvaries from about 10/20/70 to about 30/60/10, respectively, depending onfactors such as alkalinity, pH-depedent solubility, and/or eliminationhalf-life of the active ingredient.

There are instances wherein the onset of drug release should beginseveral hours following oral administration to provide adequate plasmaconcentration to be suitable for a once-daily dosing regimen, dependingon the elimination half-life of the active. In accordance withparticular aspects of the invention, drug release may be delayed for upto about 10-15 hours after oral administration.

A single targeted sustained-release profile over several hours afteroral administration, with or without an immediate release pulse, isprovided in accordance with certain of the timed pulsatile release drugdelivery systems of the present invention.

In accordance with one aspect of the invention, one or more activeingredients, a binder such as hydroxypropylcellulose (Klucel LF), adissolution rate controlling polymer (if used), and optionally otherpharmaceutically acceptable excipients are blended together in a highshear granulator such as Fielder or a fluid bed granulator such as GlattGPCG 5 and granulated to form agglomerates by adding/spraying agranulating fluid such as water or alcohol and dried. The wet mass canbe extruded and spheronized to produce spherical particles (beads) usingan extruder/marumerizer. In accordance with another embodiment of theinvention, dried granules may be compressed into pellets (i.e., mini ormicro-tablets) with a diameter of about 1 mm to 2 mm. In theseembodiments, the drug load could be as high as 95% by weight based onthe total weight of the extruded/spheronized or mini-/micro-tablet core.

In accordance with a specific embodiment, the active containing cores(beads, pellets, mini-/micro-tablets or granular particles) thusobtained are coated with a lag-time coating comprising a water-insolublepolymer and an enteric polymer, such as ethylcellulose and hypromellosephthalate (i.e., hydroxypropyl methylcellulose phthalate or HPMCP) at athickness from about 10 to 60%, more particularly from about 30% to 60%,by weight based on the total weight of the coated beads. The ratio ofwater insoluble polymer to enteric polymer may vary from about 10:1 to1:2, more particularly from about 2:1 to 1:1.

An aqueous or a pharmaceutically acceptable solvent medium may be usedfor preparing core particles. The type of inert binder that is used tobind the water-soluble drug to the inert particle is not critical butusually water-soluble or alcohol soluble binders are used.Representative examples of binders include, but are not limited to,polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose, carboxyalkylcelluloses, polyethylene oxide,polysaccharides such as dextran, corn starch, which may be dissolved ordispersed in water, alcohol, acetone or mixtures thereof. The bindersare typically used at a concentration of from about 0.5 to 10% byweight.

Representative examples of enteric polymers useful in the inventioninclude esters of cellulose and its derivatives (cellulose acetatephthalate, hydroxypropyl methylcelluose phthalate, hydroxypropylmethylcellulose acetate succinate), polyvinyl acetate phthalate,pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac.These polymers may be used as a dry powder or an aqueous dispersion.Some commercially available materials that may be used are methacrylicacid copolymers sold under the trademark Eudragit (L100, S100, L30D)manufactured by Rohm Pharma, Cellacefate (cellulose acetate phthalate)from Eastman Chemical Co., Aquateric (cellulose acetate phthalateaqueous dispersion) from FMC Corp. and Aqoat (hydroxypropylmethylcellulose acetate succinate aqueous dispersion) from Shin EtsuK.K.

Representative examples of water-insoluble polymers useful in theinvention include ethylcellulose, polyvinyl acetate (for example,Kollicoat SR #30D from BASF), cellulose acetate, cellulose acetatebutyrate, neutral copolymers based on ethyl acrylate andmethylmethacrylate, copolymers of acrylic and methacrylic acid esterswith quaternary ammonium groups such as Eudragit NE, RS and RS30D, RL orRL30D and the like.

Dissolution rate controlling polymers suitable for incorporating in theformulation for producing granules by high shear or fluid bedgranulation or by dry granulation include high molecular weighthydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose,sodium carboxymethyl cellulose, alginic acid, polymethylmethacrylatecopolymers and polyvinyl acetate/crotonic acid copolymer or combinationsthereof.

Both enteric and water-insoluble polymers used in forming the membranesare usually plasticized. Representative examples of plasticizers thatmay be used to plasticize the membranes include triacetin, tributylcitrate, triethyl citrate, acetyl-tri-n-butyl citrate, diethylphthalate, castor oil, dibutyl sebacate, acetylated monoglycerides,acetylated diglycerides and the like or mixtures thereof. Theplasticizer, when used, may comprise about 3 to 30 wt. % and moretypically about 10 to 25 wt. % based on the polymer. The type ofplasticizer and its content depends on the polymer or polymers andnature of the coating system (e.g., aqueous or solvent based, solutionor dispersion based and the total solids).

In general, it is desirable to prime the surface of the particle beforeapplying the membrane coatings or to separate the different membranelayers by applying a thin hydroxypropyl methylcellulose (HPMC) (OpadryClear) film. While HPMC is typically used, other primers such ashydroxypropylcellulose (HPC) can also be used.

The active pharmaceutical ingredients suitable for incorporation intothese time-controlled pulsatile release systems include basic bioactivemolecules or their salts. The drug substance can be selected from thegroup of pharmaceutically acceptable chemical entities with provenpharmacological activity in humans. Representative examples includeanalgesics, anticonvulsants, antidiabetic agents, anti-infective agents,antineoplastics, antiParkinsonian agents, antirheumatic stimulants,cardio vascular agents, CNS (central nervous system) stimulants,dopamine receptor agonists, gastrointestinal agents, psychetherapeuticagents, opioid agonists, opioid antagonists, urinary tract agents,antiemetics, anti-epileptic drugs, histamine H2 antagonists, skeletalmuscle relaxants, and antiasthmatic agents.

The membrane coatings can be applied to the core using any of thecoating techniques commonly used in the pharmaceutical industry, butfluid bed coating is particularly useful. The present invention isdirected to multi-dose forms, i.e., drug products in the form ofmulti-particulate dosage forms (hard gelatin capsules, conventionaltablets or ODTs (orally disintegrating tablets)) comprising one or morebead populations for oral administration to provide target PK profilesin patients in need of treatment. The conventional tablets rapidlydisperse on entry into the stomach while ODTs rapidly disintegrate inthe oral cavity forming a suspension of coated beads for easyswallowing. One or more coated bead populations may be compressedtogether with appropriate excipients into tablets (for example, abinder, a diluent/filler, and a disintegrant for conventional tabletswhile a rapidly dispersing granulation may replace thebinder-diluent/filler combination in ODTs).

The following non-limiting examples illustrate the capsule dosage formscomprising one or more pulses, each with a predetermined delayed-onsetand the totality of the in vitro drug-release profile or the ensuing invivo plasma concentration profile upon oral administration of the dosageform should mimic the desired profile to achieve maximum therapeuticefficacy to enhance patient compliance and quality of life. Such dosageforms, when administered at the ‘right time’, would enable maintainingdrug plasma concentration at a level potentially beneficial inminimizing the occurrence of side-effects associated with C_(max) orC_(min).

Example 1 (Inventive) A. IR Beads of Nizatidine

Nizatidine (168 kg) was slowly added to an aqueous solution ofhydroxypropylcellulose such as Klucel LF (18.6 kg) and mixed well.#25-30 mesh sugar spheres (107.4 kg) were coated with the drugsuspension in a Glatt fluid bed coater, equipped with a 32″ bottom sprayWurster insert. The drug containing particles were dried, and a sealcoat of Opadry Clear (2% w/w) was first applied and dried in the Glattfluid bed unit as a precautionary measure to drive off excessive surfacemoisture. The drug load was 56% w/w.

B. Nizatidine Beads with a Barrier-Coating of HPMCP:

IR beads produced above were coated in Glatt GPCG 5 equipped with abottom spray Wurster insert with HPMCP (e.g., hypromellose phthalate,HP-55 commercially available from Shin Etsu) and triethyl citrate (TEC)as a plasticizer at a ratio of 90/10 dissolved in 98/2 acetone/water fora weight gain of 10% based on the weight of the coated beads.

C. Nizatidine TPR Beads without a Barrier-Coating of HPMCP:

Drug containing IR Beads from Step A above were provided with an outermembrane by spraying a solution of 45.5/40/14.5 EC/HPMCP/TEC(ethylcellulose/HPMCP/triethylcitrate) in 98/2 acetone/water in a fluidbed coater for a weight gain of approximately 20%, 25% and 30%. Thecoated particles were unit cured at 60° C. for 10 minutes to produce TPRBeads (batch size: 4 kg).

D. Nizatidine TPR Beads with a Barrier-Coating of HPMCP:

The enteric-coated beads from Step B above were provided with an outermembrane by spraying a solution of 45.5/40/14.5 EC/HPMCP/TEC in 98/2acetone/water in a fluid bed coater for a weight gain of approximately20%, 30%, and 40%. The coated particles were unit cured at 60° C. for 10minutes to produce TPR Beads (batch size: 4 kg).

E. Nizatidine TPR Beads with a Barrier-Coating of EC/HPC:

IR beads produced above (Step A) were coated in Glatt GPCG 5 equippedwith a bottom spray Wurster insert with ethylcellulose andhydroxypropylcelluse (e.g., Klucel LF commercially available fromAqualon) at a ratio of 70/30 dissolved in acetone/water plasticized withTEC for a weight gain of 5% based on the weight of the coated beads.These barrier-coated beads were provided with an outer membrane byspraying a solution of 45.5/40/14.5 EC/HPMCP/TEC in 98/2 acetone/waterin a fluid bed coater for a weight gain of approximately 20%, 30% and40%. The coated particles were unit cured at 60° C. for 10 minutes toproduce TPR Beads (batch size: 4 kg).

Example 2 (Comparative) A. IR Beads of Propranolol HCl:

Propranolol HCl (168 kg) was slowly added to an aqueous solution ofpolyvinylpyrrolidone (8.8 kg Povidone K-30) and mixed well. 25-30 meshsugar spheres (117.2 kg) were coated with the drug solution in a Glattfluid bed granulator equipped with 32″ bottom spray Wurster insert. Thedrug containing pellets were dried, and a seal coat of Opadry Clear (6.0kg) was first applied and dried in the Glatt fluid-bed unit as aprecautionary measure to drive off excessive surface moisture. The drugload was 56% w/w.

B. Propranolol HCl Beads with a Barrier-Coating of HPMCP:

IR beads produced above were coated in Glatt GPCG 5 equipped with abottom spray Wurster insert with HPMCP and TEC at a ratio of 90/10dissolved in 98/2 acetone/water for a weight gain of 10% based on theweight of the coated beads.

C. Propranolol HCl TPR Beads (without Barrier-Coating):

IR beads produced in Step A above were coated in Glatt GPCG 5 withethylcellulose, HPMCP and triethyl citrate at a ratio of 45.5/40/14.5dissolved in 98/2 acetone/water for a weight gain of 20%, 30% and 40%based on the weight of the coated beads.

D. Propranolol HCl TPR Beads (with a Barrier-Coat of EC):

IR beads produced in Step A above were coated in fluid-bed equipment(Fluid Air FA0300 equipped with a 32″ bottom spray Wurster insert) withethylcellulose and diethyl phthalate (DEP) as a plasticizer at a ratioof 90/10 for a weight gain of 1.8% by weight. This coating was followedby a lag-time coating of EC/HPMCP/DEP at a ratio of 45.5/40/14.5dissolved in 98/2 acetone/water for a weight gain of 15%, based on theweight of the coated beads.

Drug Release Testing: The drug release profiles were generated bydissolution testing per US Pharmacopoeia method (Apparatus 1 withbaskets at 100 rpm or Apparatus 2 with paddles at 50 rpm) using 700 mLof p H 1.2 buffer for 2 hours followed by testing in 900 mL of pH 6.8for the remaining time-points). The IR and enteric-coated beads weretested in 900 mL of 0.1N HCl for 1 and 1.5 hrs, respectively. Thesamples pulled at different time-points were quantified by HPLC.

Example 3 Stability of Coated Beads:

Nizatidine TPR beads of Example 1D coated with EC/HPMCP at 40% werepackaged in induction-sealed HDPE bottles, placed on stability at 40°C./75% RH and samples were pulled at 1, 2, 3 and 6-month time points.Dissolution tests were performed using the procedures detailed above.The TPR beads stored at accelerated stability conditions exhibitedacceptable stability for at least 6 months.

Drug Release Profile:

Finished capsules may comprise one or more TPR bead populations withdesired lag-times or in combination with IR beads at a desired ratio andin sufficient quantities to provide target in vitro drug-releaseprofiles and hence target pharmacokinetics (PK) profiles suitable for atwice-daily or once-daily dosing regimen. When tested under in vitroconditions following the dissolution test procedure listed above, the IRbeads which are designed to provide a loading dose typically releasesubstantially all of the drug within the first hour, preferably withinthe first 30 minutes. The Timed Pulsatile Release (TPR) Beads aredesigned to begin releasing the drug after a lag-time of up to severalhours (a period of minimal drug-release (less than about 10% of thedose) following oral administration). The pulse may be a rapid burst orspread over a period ranging from about 2 hours to about 20 hoursdepending on the thickness of the lag-time coating and/or thebarrier-coat.

Acid-Resistance of Nizatidine and Propranolol Beads Coated with HPMCP

The enteric polymer coating applied on nizatidine IR beads of Example 1Bmore or less disintegrated within an hour releasing most of the dose inthe acidic buffer although the enteric polymer was not supposed todissolve. In contrast, the enteric-coated beads of propranololhydrochloride of Example 2B exhibited the expected acid-resistantproperty by releasing not more than 1% of the dose in 1.5 hours ofdissolution testing at pH 1.2. Although not wishing to be bound bytheory, it appears the water imbibed into the core of coated nizatidinebeads dissolves some nizatidine creating an alkaline pH environment,which tends to destroy the enteric polymer membrane on the entericcoated IR beads, even though the dissolution medium is acidic.

Effect of Barrier-Coat on Lag-Time:

From a comparison of FIGS. 1 and 2, which depict the drug-releaseprofiles of TPR beads without a barrier coat, it is clear that the TPRbeads of nizatidine, a slightly alkaline drug, coated with EC/HPMCP at30% by weight exhibits a lag-time of less than 3 hours. In contrast, theTPR beads of propranolol HCl, a slightly acidic drug, coated with thesame polymer blend at the same coating thickness exhibits a lag-time ofabout 5 hours. From a comparison of the lag-times observed fromNizatidine and propranolol HCl TPR beads at identical coating conditionsand compositions, it is evident that the acidity/alkalinity plays amajor role in providing the lag time (FIG. 3).

FIGS. 4 and 5 demonstrate the effect of a barrier coating on the lagtime that can be achieved for nizatidine beads. For example, at thecoating of 40% by weight, an enteric-polymer barrier provides a lag timeof about 5 hours while a more hydrophobic barrier of EC/HPC enablesachieving a lag time of about 8 hours. These differences become clearerfrom FIG. 6, which shows the drug-release profiles from TPR beads at 30%coating: i) with no barrier coating; ii) with a barrier coating of anenteric polymer; or iii) a hydrophobic polymer blend. It is evident thata barrier coating with a hydrophobic water-insoluble polymer such asethylcellulose provides longer lag times as compared to a barriercoating of an enteric polymer from TPR beads of alkaline drugs.

From these demonstrations, it is apparent that the alkalinity/acidity ofthe active pharmaceutical ingredient has a significant impact on the lagtime that can be achieved at given coating conditions. Another activesuch as atenolol which is more alkaline than nizatidine would beexpected to show shorter lag time than nizatidine. Of course, the lagtime can be increased by providing a barrier coating comprising anappropriate polymer alone or in combination with a membrane modifier(for example, hydrophobic ethylcellulose alone or together withwater-soluble hydroxypropylcellulose). The membrane thickness can bevaried to further fine-tune the lag time.

While the invention has been described in detail and with respect tospecific embodiments thereof, it will be apparent that numerousmodifications and variations are possible without departing from thescope of the invention as defined by the following claims.

What is claimed is:
 1. A pharmaceutical composition comprising immediaterelease (IR) beads and timed, pulsatile release (TPR) beads, wherein theTPR beads comprises: a. a core particle comprising an activepharmaceutical ingredient or a pharmaceutical acceptable salt thereof;b. an inner barrier coating comprising a water-insoluble polymer that isoptionally in combination with a water-soluble/pore-forming polymer; andc. an outer lag time coating comprising a water-insoluble polymer incombination with at least one enteric polymer.
 2. The pharmaceuticalcomposition of claim 1, wherein the immediate release beads eachcomprise a drug-containing core particle comprising said activepharmaceutical ingredient or a pharmaceutically acceptable salt thereof;wherein said immediate release beads release not less than about 90% ofsaid active pharmaceutical ingredient contained therein within the firsthour after oral administration of the pharmaceutical composition.
 3. Thepharmaceutical composition of claim 2, wherein the drug-containing coreparticle in the IR bead comprises: i. an inert particle coated with thedrug and optionally a polymeric binder; or ii. a pellet, or mini- ormicro-tablet, a microgranule, or a granular particle containing the drugand optionally a polymeric binder.
 4. The pharmaceutical composition ofclaim 1, wherein the drug-containing core particle in the TPR beadcomprises: i. an inert particle coated with the drug and optionally apolymeric binder; or ii. a pellet, or mini- or micro-tablet, amicrogranule, or a granular particle containing the drug and optionallya polymeric binder.
 5. The pharmaceutical composition of claim 4,wherein the optional polymeric binder is selected from the groupconsisting of polyvinylpyrrolidone, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, corn starch,pregelatinized starch, and mixtures thereof.
 6. The pharmaceuticalcomposition of claim 1, wherein said water-insoluble polymer is selectedfrom the group consisting of ethylcellulose, cellulose acetate,cellulose acetate butyrate, polyvinyl acetate, methylmethacrylate esterpolymers, neutral copolymers based on ethylacrylate andmethylmethacrylate, copolymers of acrylic and methacrylic acid esters,and mixtures thereof.
 7. The pharmaceutical composition of claim 1,wherein said water-insoluble polymer is a neutral copolymer based onethylacrylate and methylmethacrylate.
 8. The pharmaceutical compositionof claim 1, wherein said enteric polymer is selected from the groupconsisting of cellulose acetate phthalate, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose succinate, polyvinyl acetatephthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers,shellac, and mixtures thereof.
 9. The pharmaceutical composition ofclaim 1, wherein said enteric polymer is a mixture of pH-sensitivemethacrylic acid-methylmethacrylate copolymers.
 10. The pharmaceuticalcomposition of claim 1, wherein the ratio of said water insolublepolymer to said enteric polymer in said outer lag-time coating rangesfrom about 10:1 to about 1:3.
 11. The pharmaceutical composition ofclaim 1, wherein the ratio of said water insoluble polymer to saidenteric polymer in said outer lag-time coating ranges from about 3:1 toabout 1:1.
 12. The pharmaceutical composition of claim 1, wherein atleast one of the inner barrier coating and the outer lag-time coatingcomprises a plasticizer.
 13. The pharmaceutical composition of claim 1,wherein said optional water-soluble/pore-forming polymer is selectedfrom the group consisting of polyvinylpyrrolidone, methylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethyleneglycol, and mixtures thereof.
 14. The pharmaceutical composition ofclaim 1, wherein the amount of said outer lag-time coating is about 20%to 60% by weight of said timed, pulsatile release bead.
 15. Thepharmaceutical composition of claim 1, comprising a first population ofTPR beads and a second population of TPR beads.
 16. The pharmaceuticalcomposition of claim 15, wherein the ratio by weight of the IR beads tothe first TPR bead population to the second TPR bead population rangesfrom about 10/20/70 to about 30/60/10.
 17. The pharmaceuticalcomposition of claim 15, wherein the first population and secondpopulation of TPR beads exhibit different exhibit different in vivoplasma concentration profiles of the active pharmaceutical ingredient ora pharmaceutically acceptable salt thereof upon oral administration. 18.The pharmaceutical composition of claim 15, wherein the first populationof TPR beads exhibit a lag time of from about 3 to about 5 hours beforeonset of drug release.
 19. The pharmaceutical composition of claim 15,wherein the second population of TPR beads exhibits a lag time of fromabout 6 to about 9 hours before onset of drug release.
 20. Thepharmaceutical composition of claim 15, wherein the first population ofTPR beads exhibits a lag time of about 6 to about 9 hours before onsetof drug release, and the second population of TPR beads exhibits a lagtime of about 3 to about 5 hours before onset of drug release.
 21. Thepharmaceutical composition of claim 20, wherein the lag times result ina pharmacokinetic profile that is suitable for a once or twice-dailydosing regimen.